tbuckley/cabot-search huggingface dataset:
PB1879: OVERALL SURVIVAL OF RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH IBRUTINIB IN ALBANIA (2018-2022)
Authors: E. Calliku, A. Perolla, A. Cili, P. Pulluqi, T. Caja, A. Ivanaj
Journal: HemaSphere (2022)

Background: The survival and the outcome of the patients with refractory/relapsed Chronic Lymphocytic Leukemia, in the beginning has been limited and unsatisfactory, but has significantly improved during the last decades, with the discovery of the pathway inhibitors. The overall survival depends mostly on their response to the lines of treatments used and is patient-related and we have to take in consideration also the numbers of chemotherapies applied. The significant benefit of Ibrutinib approved in 2014 as a target therapy for all the patients with Chronic Lymphocytic Leukemia who has been treated previously with at least one line of therapy has been shown across all the risk groups, as demonstrated in the RESONATE study. Aims: Our study aims to evaluate the Overall Survival (OS) of all the refractory/relapsed Chronic Lymphocytic Leukemia patients treated with Ibrutinib in the third line of therapy from 2018 until january 2022 and evaluate the correlation of this survivance with the age subgroups and gender. Methods: We studied all the patients diagnosed in our University Hospital Center “Mother Teresa” in Tirana, Albania with R/R CLL who started the treatment with ibrutinib, in combination or not with immunotherapy from July 2018 until January 2022 from age >18 years old and up. We collected the data from the registries and database of Hematology Clinic. The data were analysed with SPSS variant 25. Results: From July 2018 until January 2022 we have treated with Ibrutinib third line 46 patients diagnosed with R/R CLL, 32 (69.6%) were males and 14 (30.4%) were females with a ratio M/F of about 2:1 with a median age of 63 ± 7.4 (range 43 – 80) years old. The estimated median Overall Survival resulted of 28 ± 4.9 (95%CI range 18- 37) months. Overall survival estimated according to age subgroups was higher in the 50-59 yo subgroup resulting in 38 ± 7.7 (95%CI range 16- 39) months. The differences of overall survival of the patients with R/R CLL treated with ibrutinib in the third line depending on gender were non significant Image:Summary/Conclusion: Chronic Lymphocytic Leukemia is the most common type of leukemia in the western countries and with the median age at the diagnosis of 72 years old and diagnosed more in males than in the females1. In 2013 Byjrd JC et al published in N Engl J Med that the response to Ibrutinib of R/R CLL patients previously treated was independent of clinical and genomic factors with an OS 83% at 26 months. In our study we found a median younger age of the patients at the moment of the diagnostication (median age of 63 years old) compared with the literature and a ratio male:femato 2:1. The median overall survival resulted 28 ± 4.9 (95%CI range 18- 37) months In our study found also that gender does not influence the overall survival of the patients with R/R CLL treated with ibrutinib in the third line.
Chronic Abdominal Pain and Anemia in a 59-Year-Old Man
Authors: Takashi Oshima, Kiyoshi Kinjo, Mitsuyo Kinjo
Journal: JAMA (2022)

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PB2001: A LOOK INTO THE REAL WORLD: PICTURE OF NEWLY DIAGNOSED MULTIPLE MYELOMA TRANSPLANT INELIGIBLE TREATED PATIENTS IN THE FRONTLINE SETTING. CARINAE STUDY
Authors: F. de Arriba de la Fuente, M. T. Hernández Garcia, J. A. Soler Campos, H. R. Susana, M. J. Moreno Belmonte, M. González Pardo, M. Gironella Mesa, M. Casanova Espinosa
Journal: HemaSphere (2022)

Background: Multiple myeloma (MM) is the second most common blood cancer, with an estimated 5-year prevalence of nearly 230,000 cases worldwide. MM is most frequently diagnosed among people >65 years of age and the median age at onset in Europe is 72 years.Despite the significant proportion of older patients with newly diagnosed multiple myeloma (NDMM), most clinical trials (CT) driving therapeutic decisions in routine practice include younger and presumably healthier patients than those in the real-world. Furthermore, longitudinal studies transplant-ineligible (TNE) elderly patients with MM showed limited data describing the benefit from new anti-MM agents. Aims: To try to respond to this need in the real practice of MM treatment, we share for the first time a new observational study called Carinae, that describes the clinical practice in TNE-NDMM in Spain. These results aim to help clinicians in optimizing treatment approaches for patients with MM. Methods: Observational, ambispective, descriptive study with 110 TNE-NDMM patients who started antineoplastic treatment within daily clinical practice. To describe the efficacy and safety of monoclonal antibodies (mAb) in daily clinical practice, the results collected in two patient groups before and after the availability of the DVMP, the first and only mAb approved for the treatment of TNE-NDMM in Spain. Group A: N =53 starts treatment between Sep/01/2018 and Aug/31/19 with a combination of ≥2 drugs. Group B: N =57 starts treatment between Sep/01/19 and Nov/30/20 with daratumumab in combination with bortezomib, melphalan and prednisone (daratumumab-VMP). This analysis shows a representative population of the patients in real clinical practice in Spain and analyzes the similarities and differences in the efficacy and safety of the treatments under study (with and without monoclonal antibody), for the first months. Since the follow-up of the patients has not yet been completed, deeper analysis will be presented in the future. Results: 110 NTE MM patients have been registered in Carinae study. Table 1 describes demographic and multiple myeloma at diagnosis characteristics. Updated data on effectiveness and tolerability will be presented during the Congress. Image:Summary/Conclusion: New treatments have been incorporated into the therapeutic scenario of TNE-NDMM in the last years. For the first time, a large real-world evidence study describes their incorporation in clinical practice in Spain. Our aim through the Carinae study is to provide meaningful insights about standard of care regimens with monoclonal antibodies as DVMP for TNE-NDMM patients in the real-world practice in Spain.
P1540: STUDY OF MIRNA EXPRESSION PROFILES IN GAUCHER PATIENTS AND THEIR RELATIONSHIP WITH THE SEVERITY OF BONE INVOLVEMENT
Authors: I. Serrano-Gonzalo, L. López de Frutos, M. Roca-Espiau, R. Köhler, P. Giraldo
Journal: HemaSphere (2022)

Background: Bone manifestations are one of the most prevalent comorbidities in Gaucher disease (GD) and, compromise the quality of life. They are evaluated by DEXA and MRI and several scores are available to assess its severity. Nowadays, no good biomarkers are available for this complication. miRNA are small non-coding RNA molecules whose function is regulate gene expression, and several of them were related to bone disease. Aims: Identify different miRNA expression patterns, depending on the severity of bone involvement in patients with GD and, evaluate its predictive value. Methods: 60 GD naïve patients, were selected and classified according to their bone disease severity using the S-MRI score, considering mild bone disease (MiBD; S-MRI<5), moderate (MoBD; S-MRI: 5-11) and, severe (SBD; S-MRI>11). miRNA was obtained from plasmatic exosomes using miRCURY Exosome Serum/Plasma and miRNeasy Serum/Plasma Advanced kits (QIAGEN) following manufacturer instructions. NGS technology and principal component analysis, corrected by sex and age, were applied to determine miRNA expression profiles. Results: Patients were distributed proportionally in each group (20-20-20), gender distribution was equal between groups, and age was [median (Q1-Q3)]: 19.0 (4.00-40.00) – 40.5 (28.25-56.00) – 37.5 (31.25-47.00) years for MiBD, MoBD and SBD respectively. When compared MiBD against MoBD 3 miRNA were downexpressed in the MoDB group meanwhile 1 was increased. When MiBS vs SBD were compared 4 miRNA were downregulated and 5 increased on the SBD group. Only one miRNA is upregulated on MoDB and even more so in the SBD. Summary/Conclusion: One miRNA, related inversely with osteoblastic differentiation is increased according with the bone severity. So, those preliminary results show an altered miRNA expression depending on the bone severity. Nowadays, we are validating them and trying to predict target-genes and the biological pathway they are involve. Disclosure: Project founded by a Sanofi’s grant (SGZ-2019-12810).
P446: USE OF MIRNA EXPRESSION PATTERNS REVEALS ACTIVIN RECEPTOR 2 PATHWAY IN MEDIATING CHEMO-RESISTANT AML
Authors: P. Reichelt, S. Bernhart, F. Wilke, U. Platzbecker, M. Cross, G. Behre
Journal: HemaSphere (2022)

Background: Acute myeloid leukemia (AML) is a highly aggressive and heterogeneous disease and the most prevalent type of acute leukemia in adults. Standard chemotherapy using cytarabine and idarubicin/daunorubicin usually achieves remission, but this is commonly followed by chemoresistance and relapse. The treatment of chemoresistant AML remains a major challenge that will require personalized approaches. Aims: With this study, we aim to establish NGS microRNA expression profiling and pathway analysis to identify pathways that are regulated differentially between chemo-sensitive and -resistant AML as potential targets for targeted therapy. Methods: MicroRNA expression profiles were analyzed by NGS (next generation sequencing) of chemo-resistant and -sensitive subclones of AML cell line HL60. Bioinformatical identification of candidate deregulated pathways was performed using miRTarbase and stringdb. Pathway activity in cell sublines was assessed by protein expression, proliferation and flow cytometric analysis, using western blotting, phosphlow and MTS assays. Paired samples of AML pre- and post- relapse were used to validate gene expression changes by qPCR and analyses were extended to the publically available dataset of the AML patient cohort of the cancer genome atlas (TCGA). Results: Our microRNA based bioinformatic approach predicted 27 KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways to be represented differentially between resistant and sensitive cells (FDR<0.05). Prominent among these were significant changes in signaling pathways of the TGFβ ligand family. Cell culture experiments and protein expression analysis confirmed both a higher sensitivity to TGFβ induced growth arrest and increased abundance of TGFβ signaling proteins in chemo-resistant HL60 cells. Consistent differences in TGFß pathway gene expression were also detected in AML patients of the TCGA dataset. Furthermore, our data suggest a shift of the predominantly expressed isoform of activin receptor 2B to activin receptor 2A in chemo-resistance. Analysis of paired bone marrow samples from AML patients at diagnosis and first relapse showed the latter to be associated with higher expression of TGFβ receptors and the TGFβ target protein CDKN2B as well as significant upregulation of activin receptor 2A. Image:Summary/Conclusion: Here we show how miRNA screening approaches can be used to predict deregulated cellular signaling pathways as potential targets for the therapy of chemoresistant AML. MicroRNA based prediction of targetable pathways combined with database screening identified the activin receptor 2A/B as a potential modulator of chemoresistance.
PB1994: REAL WORLD DATA OF PATIENTS WITH MULTIPLE MYELOMA WITHOUT ACCESS A NOVEL AGENT IN FIRST LINE THERAPY IN PUBLIC HEALTH HOSPITAL IN MEXICO
Authors: D. Cruz, G. SOTOMAYOR, L. G. AVILA
Journal: HemaSphere (2022)

Background: Real World data of patients with Multiple Myeloma without access a novel agent in first line therapy in public Health hospital in Mexico Aims: To expose the 5-year OS and PFS of patients with multiple myeloma who did not use Bortezomib as first line therapy and to compare its use after first line. Methods: Observational, longitudinal and retrospective study. Measures of central tendency, Kaplan-Meier curves with Log-Rank as well as Cox regression were performed for survival analysis, with HR report, ranges were obtained considering significant a value of p <0.05 with 95% CI. 0.1 amplitude with 5% error Results: 265 patients, 126 (47.5%) male and 139 (52.5%) female, with a median age of 62 years (34-90). The 5-year OS was 47%. In PFS 55% at 1 year and 9% at 5 years. In comparison OS of subsequent line with Bortezomib versus absence, OS of 59% was reported in the Bortezomib arm versus 43% with HR of 1.819 (95% CI 1.235-2.677) with a P value of P=0.002. Summary/Conclusion: The absence of proteosome inhibitor as first line negatively impacts OS and PFS; its use even as subsequent line therapy may improve prognosis
PB2166: TET ENZYMES PROTECT AGAINST FATAL LYMPHOPROLIFERATION
Authors: S. Spoeck, N. Kinz, A. Villunger, V. Labi
Journal: HemaSphere (2022)

Background: The most common epigenetic modification in eukaryotic genomes is methylation of cytosine. TET enzymes, of which TET2 and TET3 are expressed throughout the immune system, facilitate DNA demethylation via oxidation of 5-methylcytosine in DNA to 5-hydroxymethylcytosine and iterative oxidative species. These oxidized variants ameliorate chromatin accessibility and transcriptional activity by enabling DNA demethylation or serving as epigenetics marks on their own. In the immune system and beyond, TET enzymes serve to establish and adapt cell identity programs during lineage specification. In human leukemias and lymphomas, TET2 is one of the most frequent mutated genes, and TET3 gene variants are associate with the most common autoimmune disorder, systemic lupus erythematosus (SLE). Thus, in humans, loss of TET activity associates with different pathologies of the hematopoietic and immune systems. In mice, TET2 loss-of-function promotes inflammation and boosts oncogene-driven lymphomas and leukemias. However, the kinetic and nature of molecular and cellular changes upon TET loss-of-function remain ill-defined. Aims: Ultimately, our work aims to identify therapeutic entry points for hematologic and immune pathologies with impaired TET activity. Methods: In our lab, we employ cell culture systems and pre-clinical mouse models to elucidate pathophysiological mechanisms that underlie TET loss-of-function driven pathologies originating from B lymphocytes. Results: We have established that TET2 and TET3 synergize in stabilizing DNA methylation patterns and transcriptional programs that guard cell identity while B lymphocytes transit through developmental stages, allowing the generation of functional B lymphocytes. Furthermore, the joint deletion of TET2 and TET3 specifically in antigen-activated B lymphocytes drives combined immunodeficiency and autoimmunity already in young mice. When aging, a fatal lymphadenopathy with 100% penetrance arises, which also involves TET-proficient immune cells such as T lymphocytes. Summary/Conclusion: Our data suggest that diminished TET activity in antigen-activated B lymphocytes critically determines optimal humoral immune responses and predisposes to fatal lymphoproliferation.
PB1811: BIOLOGIC AND CLINICAL SIGNIFICANCE OF CD7 ABERRANT EXPRESSION IN ACUTE MYELOID LEUKEMIA: A POOR PROGNOSIS MARKER
Authors: H. Charfi, N. Louati, G. Baccar, O. Kassar, N. Siala, Y. Fakhfakh, M. Chaari, M. Ellloumi, J. Gargouri, H. Menif, T. Rekik, I. Ben amor
Journal: HemaSphere (2022)

Background: CD7, a T-cell lineage associated antigen, is the most commonly expressed lymphoid antigen in acute myeloid leukemia (AML). There have been conflicting reports in the literature on its expression’s frequencies in AML and whether it may impact treatment response and survival. Aims: To identify the clinical and biological features of CD7+ AML, and evaluate the association of CD7 aberrant expression with response rates and survival parameters. Methods: We retrospectively reviewed data from patients diagnosed with de novo AML in our laboratory during january 2013 and december 2020. Acute promyelocytic leukemia was not included in our study. CD7 expression was established by flow cytometry (bone marrow or peripheral blood samples) using a cut-off of > 20%, firstly on Epics XL cytometre (BC) then on FACS Canto II (BD). Patients demographics, AML characteristics, response to treatment and follow up data were collected. Only patients under the age of 60 were intensively-treated in our center. End points were complete remission (CR), overall survival, event free survival (EFS) and relapse rate. Survival statistical analysis performed with Kaplan Meyer method. Results: A total of 138 patients were included, of whom 41 (29%) expressed CD7 (9 children and 32 adults). The median age was 7 years and 44 years respectively, with male/female ratio of 1.5. CD7 aberrant expression was significantly associated with an inferior white cells count at diagnosis (9.5 vs 29 G/L, p=0.018), the presence of tumoral syndrome such as adenopathies (24% vs 9%, p=0.02), a FAB M2 classification (34% vs 20%, p=0.028), and the expression of immaturity antigen CD34 (80% vs 54%, p=0.05). Eleven percent (vs 37%, p=0.018), 68% (vs 58%) and 21% (vs 15%) of the cases belonged to the favourable, intermediate (of which a normal karyotype was found in 69% of cases (vs 62%, p=0.03)) and unfavourable cytogenetic categories respectively. Lymphoid cytogenetic abnormalities performed (11q23, t(9;22), t(1;19)) were not detected. CD7 positivity adversely affected both the OS and EFS at 5 years (26% vs 43%, p=0.05 and 27% vs 49% p=0.04 respectively), with an inferior CR rate to induction (43% vs 65% p=0.1) and a higher relapse rate (37% vs 21%, p=0.2). By multivariate cox regression, CD7 expression (HR 1.6; p=0.08) represent an independent predictor of mortality. Summary/Conclusion: Our results were similar to those of the literature with regard to the frequency of aberrant expression of CD7 in AML (10 to 40%), the frequency of association of CD7+ AML with type M2 and its association with immature antigen CD34 but not with lymphoid cytogenetic abnormalities. The expression of this lymphoid marker in our AML was correlated with prognosis in terms of response to treatment and survival. CD7 expression may be so useful for therapeutic decision algorithms.
Bipolar Metal Flexible Electrospun Fibrous Membrane Based on Metal–Organic Framework for Gradient Healing of Tendon‐to‐Bone Interface Regeneration (Adv. Healthcare Mater. 12/2022)
Authors: Renhao Yang, Yunlong Zheng, Yin Zhang, Gen Li, Yidong Xu, Yin Zhang, Yang Xu, Chengyu Zhuang, Pei Yu, Lianfu Deng, Wenguo Cui, Yao Chen, Lei Wang
Journal: Advanced Healthcare Materials (2022)

Bioscaffolds This schematic diagram is to illustrate the repair effect of a bipolar fibrous membrane in the ink painting style with Chinese characteristics. The sky and ground on both sides of the fibrous membrane respectively represents tendon and bone. Both the MOF particles in the bipolar fibrous membrane can promote tissue repair, and the phoenix is used to highlight the repair effect of MOF particles. This work can be found in article number 2200072 by Wenguo Cui, Yao Chen, Lei Wang, and co-workers.
Tumor Immune Microenvironment Changes by Multiplex Immunofluorescence Staining in a Pilot Study of Neoadjuvant Talazoparib for Early-Stage Breast Cancer Patients with a Hereditary <i>BRCA</i> Mutation
Authors: Tapsi Kumar, Evie Hobbs, Fei Yang, Jeffrey T. Chang, Alejandro Contreras, Edwin Roger Parra Cuentas, Haven Garber, Sanghoon Lee, Yiling Lu, Marion E. Scoggins, Beatriz E. Adrada, Gary J. Whitman, Banu K. Arun, Elizabeth A. Mittendorf, Jennifer K. Litton
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The immunological profile of early-stage breast cancer treated with neoadjuvant PARP inhibitors has not been described. The aim of this study was to delineate the changes in the tumor immune microenvironment (TiME) induced by talazoparib. Patients and Methods: Patients with operable germline BRCA1/2 pathogenic variant (gBRCA1/2+) breast cancer were enrolled in a feasibility study of neoadjuvant talazoparib. Thirteen patients who received 8 weeks of neoadjuvant talazoparib were available for analysis, including 11 paired pre- and post-talazoparib core biopsies. Treatment-related changes in tumor-infiltrating lymphocytes were examined and immune cell phenotypes and their spatial distribution in the TiME were identified and quantified by multiplex immunofluorescence using a panel of 6 biomarkers (CD3, CD8, CD68, PD-1, PD-L1, and CK). Results: Neoadjuvant talazoparib significantly increased infiltrating intratumoral and stromal T-cell and cytotoxic T-cell density. There was no difference in PD-1 or PD-L1 immune cell phenotypes in the pre- and post-talazoparib specimens and PD-L1 expression in tumor cells was rare in this cohort. Spatial analysis demonstrated that pre-talazoparib interactions between macrophages and T cells may correlate with pathologic complete response. Conclusions: This is the first study with phenotyping to characterize the immune response to neoadjuvant talazoparib in patients with gBRCA1/2+ breast cancer. These findings support an emerging role for PARP inhibitors in enhancing tumor immunogenicity. Further investigation of combinatorial strategies is warranted with agents that exploit the immunomodulatory effects of PARP inhibitors on the TiME.
Effects of Coronary Artery Disease–Associated Variants on Vascular Smooth Muscle Cells
Authors: Charles U. Solomon, David G. McVey, Catherine Andreadi, Peng Gong, Lenka Turner, Paulina J. Stanczyk, Sonja Khemiri, Julie C. Chamberlain, Wei Yang, Tom R. Webb, Christopher P. Nelson, Nilesh J. Samani, Shu Ye
Journal: Circulation (2022)

Genome-wide association studies have identified many genetic loci that are robustly associated with coronary artery disease (CAD). However, the underlying biological mechanisms are still unknown for most of these loci, hindering the progress to medical translation. Evidence suggests that the genetic influence on CAD susceptibility may act partly through vascular smooth muscle cells (VSMCs).